Hsp90 inhibitors

ABSTRACT

The disclosure relates to Compounds of Formula (1): 
                         
and pharmaceutically acceptable salts thereof wherein Z 1 , Z 2 , Z 3 , Xa, Xb, Xc, Y, X 2 , and X 4  are as defined herein, compositions comprising an effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof, and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof.

This application is a divisional of U.S. application Ser. No.14/110,095, filed Oct. 4, 2013, now U.S. Pat. No. 9,546,170, which is anational phase of PCT/US2012/032373, filed April 5, 2012, which claimsthe benefit of and priority from U.S. provisional application no.61/472,061, filed Apr. 5, 2011, the contents of which are incorporatedherein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant numberAG032969 awarded by National Institutes of Health. The government hascertain rights in the invention.

1 BACKGROUND

This application relates to compounds that inhibit heat shock protein 90(Hsp90).

The Hsp90 family of proteins has four recognized members in mammaliancells: Hsp90 α and β, Grp94 and Trap-1. Hsp90 α and β exist in thecytosol and the nucleus in association with a number of other proteins.Hsp90 in its various forms is the most abundant cellular chaperone, andhas been shown in experimental systems to be required for ATP-dependentrefolding of denatured or “unfolded” proteins. It has therefore beenproposed to function as part of the cellular defense against stress.When cells are exposed to heat or other environmental stresses, theaggregation of unfolded proteins is prevented by pathways that catalyzetheir refolding or degradation. This process depends on the associationof the unfolded protein in an ordered fashion with multiple chaperones(Hsp60, Hsp90, Hsp70 and p23), forming a “refoldosome” and ultimatelythe ATP-dependent release of the chaperones from the refolded protein.

Hsp90 can also play a role in maintaining the stability and function ofmutated proteins. It seems to be required for expression of mutated p53and v-src to a much greater extent than for their wild-typecounterparts. It has been suggested that this occurs as a result ofHsp90-mediated suppression of the phenotypes of mutations that lead toprotein unfolding.

Hsp90 is also necessary to the conformational maturation of several keyproteins involved in the growth response of the cell to extracellularfactors. These include the steroid receptors as well as certain kinases(i.e., Raf serine kinase, v-src and Her2). The mechanism whereby Hsp90affects these proteins is not fully understood, but appears to besimilar to its role in protein refolding. In the case of theprogesterone receptor, it has been shown that binding and release ofHsp90 from the receptor occurs in a cyclic fashion in concert withrelease of other chaperones and immunophilins and is required for highaffinity binding of the steroid to the receptor. Thus, Hsp90 couldfunction as a physiologic regulator of signaling pathways, even in theabsence of stress.

Hsp90 has been shown to be overexpressed in multiple tumor types and asa function of oncogenic transformation. Whether it plays a necessaryrole in maintaining transformation is unknown, but it could have atleast three functions in this regard. Cancer cells grow in anenvironment of hypoxia, low pH and low nutrient concentration. They alsorapidly adapt to or are selected to become resistant to radiation andcytotoxic chemotherapeutic agents. Thus, the general role of Hsp90 inmaintaining the stability of proteins under stress may be necessary forcell viability under these conditions. Secondly, cancer cells harbormutated oncogenic proteins. Some of these are gain-of-function mutationswhich are necessary for the transformed phenotype. Hsp90 may be requiredfor maintaining the folded, functionally-active conformation of theseproteins. Thirdly, activation of signaling pathways mediated by steroidreceptors, Raf and other Hsp90 targets is necessary for the growth andsurvival of many tumors which thus probably also require functionalHsp90.

Hsp90 has been recognized as a viable target for therapeutic agents.Hsp90 family members possess a unique pocket in their N-terminal regionthat is specific to and conserved among all Hsp90s from bacteria tomammals, but which is not present in other molecular chaperones. Theendogenous ligand for this pocket is not known, but it binds ATP and ADPwith low affinity and has weak ATPase activity. The ansamycinantibiotics geldanamycin (GM) and herbimycin (HA) have been shown tobind to this conserved pocket, and this binding affinity has been shownfor all members of the Hsp90 family. International Patent PublicationNo. WO98/51702 discloses the use of ansamycin antibiotics coupled to atargeting moiety to provide targeted delivery of the ansamycin leadingto the degradation of proteins in and death of the targeted cells.International Patent Publication No. WO00/61578 relates to bifunctionalmolecules having two moieties which interact with the chaperone proteinHsp90, including in particular homo- and heterodimers of ansamycinantibiotics. These bifunctional molecules act to promote degradationand/or inhibition of HER-family tyrosine kinases and are effective fortreatment of cancers which overexpress Her-kinases.

Exemplary small molecule therapeutics that bind to the same bindingpocket of Hsp90 as ATP and the ansamycin antibiotics are disclosed inPCT Publication Nos. WO02/36075, WO2006/084030, WO2009/042646,WO2009/065035, and WO2011/044394; U.S. Pat. No. 7,834,181; and U.S.Patent Publication Nos. 2005/0113339, 2005/0004026, 2005/0049263,2005/0256183, 2005/0119292, 2005/0113340, 2005/0107343, 2008/0096903,2008/0234297, 2008/0234314, 2008/0253865, and 2009/0298857, all of whichare incorporated herein by reference.

In particular, certain small molecule therapeutics that bind to the samebinding pocket of Hsp90 can be described by the following generalstructural formula where Z₁, Z₂, and Z₃ are selected from CH and N:

While these compounds can be active as inhibitors of Hsp90, their levelof activity is extremely variable with measured values for EC₅₀ and IC₅₀being reported in anywhere from the micromolar to nanomolar ranges.

2 SUMMARY

In one aspect of the disclosure, new compounds that inhibit Hsp90 aredescribed.

A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   (a) each of Z₁, Z₂ and Z₃ is independently CH or N;    -   (b) Y is S;    -   (c) Xa and Xb are O;    -   (d) Xc is —CH₂—;    -   (e) X₂ is —NR₁R₂, wherein R₁ and R₂ are each independently H,        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl,        arylalkyl, alkylheteroaryl, heteroarylalkyl, or        alkylheteroarylalkyl;    -   (f) X₄ is hydrogen or halogen; and    -   (g) R is R₁₀—NH—R₁₁ wherein R₁₀ is ethylene or propylene, and        R₁₁ is a branched alkyl.

The compounds are useful in pharmaceutical compositions for thetreatment of cancer and neurodegenerative diseases through theiractivity as Hsp90 inhibitors and can be used in a method of treatingcancer or neurodegenerative diseases.

3 DETAILED DESCRIPTION

The invention includes the following:

(1) A Compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   (a) each of Z₁, Z₂ and Z₃ is independently CH or N;    -   (b) Y is S;    -   (c) Xa and Xb are O;    -   (d) X is —CH₂—;    -   (e) X₂ is —NR₁R₂, wherein R₁ and R₂ are each independently H,        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl,        arylalkyl, alkylheteroaryl, heteroarylalkyl, or        alkylheteroarylalkyl, or a protonated form thereof;    -   (f) X₄ is hydrogen or halogen; and    -   (g) R is —R₁₀—NH—R₁₁ wherein R₁₀ is ethylene or propylene, and        R₁₁ is a branched alkyl.

(2) Compounds of (1) in which Z₁, Z₂ and Z₃ are all N as shown informula (2)

or a pharmaceutically acceptable salt thereof.

(3) Compounds of (1) or (2) or a pharmaceutically acceptable saltthereof in which R₁₁ is neopentyl, isopropyl or t-butyl.

(4) Compounds of one of the above (1) to (3) or a pharmaceuticallyacceptable salt thereof in which X₂ is dimethylamine.

(5) A pharmaceutical composition comprising the compound as in one ofthe above (1) to (5) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

(6) A method for treating or preventing cancer or a neurodegenarativedisorder, comprising administering to a patient in need thereof atherapeutically effective amount of a compound as in one of the above(1) to (5) or a pharmaceutically acceptable salt thereof.

(7) Use of a compound as in one of the above (1) to (5) or apharmaceutically acceptable salt thereof in formulating a pharmaceuticalcomposition for the treatment or prevention of cancer or aneurodegenerative disorder.

(8) A method for the inhibition of Hsp90, comprising contacting Hsp90with an Hsp90 function inhibiting amount of a compound as in one of theabove (1) to (5) or a pharmaceutically acceptable salt thereof.

(9) Use of a compound as in one of the above (1) to (5) or apharmaceutically acceptable salt thereof in formulating a pharmaceuticalcomposition for the inhibition of Hsp90.

As stated above, the disclosure encompasses Compounds of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   (a) each of Z₁, Z₂ and Z₃ is independently CH or N;    -   (b) Y is S;    -   (c) Xa and Xb are O;    -   (d) Xc is —CH₂—    -   (e) X₂ is —NR₁R₂, wherein R₁ and R₂ are each independently H,        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl,        arylalkyl, alkylheteroaryl, heteroarylalkyl, or        alkylheteroarylalkyl, or a protonated form thereof;    -   (f) X₄ is hydrogen or halogen; and    -   (g) R is —R₁₀—NH—R₁₁ wherein R₁₀ is ethylene or propylene, and        R₁₁ is a branched alkyl.

Definitions

As used in connection with the present disclosure, the terms used hereinhave the following meaning:

The terms “alkyl” and “substituted alkyl” are interchangeable unlessotherwise specifically noted and refer to substituted and unsubstitutedC₁-C₁₀ straight-chain saturated aliphatic hydrocarbon groups, i.e.,groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, andsubstituted and unsubstituted C₃-C₁₀ branched saturated aliphatichydrocarbon groups, i.e., groups having 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms. For example, “alkyl” includes but is not limited to:methyl (Me), ethyl (Et), propyl (Pr), isopropyl, butyl (Bu), tert-butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. In oneembodiment, an alkyl is a C₁-C₆ alkyl, i.e., a group having 1, 2, 3, 4,5, or 6 carbon atoms. An alkyl can be substituted with 1, 2, or 3substituents or optionally substituted with 1, 2, or 3 substituents.Illustrative examples of substituted C₁-C₆ alkyl groups include —CH₂OH,—CF₂OH, —CH₂C(CH₃)₂C(O)OCH₃, —CF₃, —C(O)CF₃, —C(O)CH₃, —(CH₂)₄SCH₃,—CH(C(O)OH)CH₂CH₂C(O)N(CH₃)₂, —(CH₂)₅NHC(O)NH₂,—CH₂CH₂-(4-fluorophenyl), —CH(OCH₃)CH₂CH₃, —CH₂SO₂NH₂, and—CH(CH₃)CH₂CH₂OC(O)CH₃. The term “branched alkyl” encompasses alkylgroups that are linear alkyl groups attached through a non-terminalcarbon atom as well as alkyl groups that include a defined branch point.Illustrative examples of branched alkyl groups thus include isopropyl,isobutyl, sec-butyl, t-butyl, isopentyl, sec-pentyl, t-pentyl, andneopentyl groups. The terms “alkenyl” and “substituted alkenyl” areinterchangeable unless otherwise specifically noted and refer tosubstituted and unsubstituted C₂-C₁₀ straight-chain aliphatichydrocarbon groups having 1, 2, or 3 carbon-carbon double bonds, i.e.,groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, andsubstituted and unsubstituted C₃-C₁₀ branched aliphatic hydrocarbongroups having 1, 2, or 3 carbon-carbon double bonds, i.e., groups having3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example, “alkenyl” includesbut is not limited to: ethenyl, 1-prop-1-enyl, 1-prop-2-enyl,2-prop-1-enyl, 1-but-3-enyl, 2-pent-2-enyl, 1-hex-6-enyl, 1-hept-7-enyl,1-oct-8-enyl, and the like. In one embodiment, an alkenyl is a C₂-C₆alkenyl, i.e., a group having 2, 3, 4, 5, or 6 carbon atoms and 1 or 2carbon-carbon double bonds. An alkenyl can be substituted with 1, 2, or3 substituents or optionally substituted with 1, 2, or 3 substituents.Illustrative examples of substituted C₂-C₆ alkenyl groups include—C(H)═CHCH₂—OH, —C(H)═CF₂, —CH₂C(H)═CH(CH₂)₂CF₂OH, —CH₂C(═CH₂)C(O)OCH₃,—C(H)═CHCF₃, —CH₂CH₂C(H)═CHC(O)CH₃, —C(H)═C(CH₃)SCH₃,—C(H)═CHC(H)═C(CH₃)C(O)OCH₃, and —C(H)═C═CHOC(O)CH₃.

The terms “alkynyl” and “substituted alkynyl” are interchangeable unlessotherwise specifically noted and refer to substituted and unsubstitutedC₂-C₁₀ straight-chain aliphatic hydrocarbon groups having 1, 2, or 3carbon-carbon triple bonds, i.e., groups having 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 carbon atoms, and substituted and unsubstituted C₃-C₁₀ branchedaliphatic hydrocarbon groups having 1, 2, or 3 carbon-carbon triplebonds, i.e., groups having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Forexample, “alkynyl” includes but is not limited to: ethynyl,1-prop-1-ynyl, 1-prop-2-ynyl, 2-prop-1-ynyl, 3-prop-1-ynyl,1-but-3-ynyl, 2-pent-2-ynyl, 1-hex-6-ynyl, 1-hept-7-ynyl, 1-oct-8ynyl,and the like. In one embodiment, an alkynyl is a C₂-C₆ alkynyl, i.e., agroup having 2, 3, 4, 5, or 6 carbon atoms and 1 or 2 carbon-carbontriple bonds. An alkynyl can be substituted with 1, 2, or 3 substituentsor optionally substituted with 1, 2, or 3 substituents. Illustrativeexamples of substituted C₂-C₆ alkynyl groups include —C≡CCH₂OH, —C≡CF,—CH₂C≡C(CH₂)₂CF₂OH, —C≡CCH₂C(O)OCH₃, —CH₂C≡CCF₃, —CH₂CH₂C≡CC(O)CH₃,—C≡CSCH₃, and —C≡CC(O)OC(O)CH₃.

The terms “cycloalkyl” and “substituted cycloalkyl” are interchangeableunless otherwise specifically noted and refer to a mono- or multi-ringedcarbocycle wherein each ring contains 3, 4, 5, 6, 7, 8, 9, or 10 carbonatoms, and wherein any ring can contain 1, 2, or 3 carbon-carbon doubleor triple bonds. For example, “cycloalkyl” includes but is not limitedto: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl,cycloalkynyl, and cycloheptyl. A cycloalkyl can be substituted with 1,2, or 3 substituents or optionally substituted with 1, 2, or 3substituents.

The terms “aryl” and “substituted aryl” are interchangeable unlessotherwise specifically noted and refer to a monocyclic, polycyclic,biaryl aromatic groups covalently attached at any ring position capableof forming a stable covalent bond, certain preferred points ofattachment being apparent to those in the art (e.g., 3-phenyl,4-naphthyl, and the like). An aryl can be substituted with 1, 2, or 3substituents or optionally substituted with 1, 2, or 3 substituents. Thedefinition of “aryl” includes but is not limited to heteroaryl.Illustrative examples of aryl groups include phenyl, biphenyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl,anthryl, phenanthryl, fluorenyl, pyrenyl, anthracenyl, pyridyl,pyrimidyl, pyridizinyl, thiadiazolyl, and the like.

The term “heteroalkyl” refers to an alkyl group where one or more of thecarbon atoms or hydrogen atoms present is replaced, independently, witha nitrogen, oxygen, sulfur, or halogen heteroatom. If the heteroatomdoes not have the same number of valence sites as the carbon atom itreplaces, the number of hydrogens bonded to the replacement heteroatommay need to be increased or decreased to match the number of valencesites of the heteroatom. For example, if a carbon atom (with a valenceof four) is replaced by a nitrogen atom (valence of three), one of thehydrogen atoms formerly attached to the replaced carbon is deleted.Likewise, if a carbon atom is replaced by a halogen atom (valence ofone), three of the hydrogen atoms formerly attached to the replacedcarbon is deleted. The term “heteroalkyl” also refers to (1) an alkylgroup where at least one of the hydrogen atoms attached to a carbon or(2) to a heteroalkyl group where at least one of the hydrogen atomsattached to a heteroatom of the heteroalkyl can be substituted with atleast one of the following: alkyl, aryl, and heteroalkyl.

The terms “heteroaryl” and “substituted heteroaryl” are interchangeableunless otherwise specifically noted and the terms “heterocyclo” and“substituted heterocyclo” are interchangeable unless otherwisespecifically noted and these terms refer to a monovalent unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 8carbon atoms, and from 1 to 4 heteroatoms within the ring, eachheteroatom being independently selected from nitrogen, sulfur, oroxygen. In either heteroaryl or heterocyclo, the point of attachment tothe molecule can be at a heteroatom or elsewhere within the ring. Aheteroaryl or heterocyclo can be substituted with 1, 2, or 3substituents or optionally substituted with 1, 2, or 3 substituents.

Illustrative examples of heteroaryl groups include thienyl,benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl,benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,pyrrol-3-yl, pyrrol-1-yl, indolyl, isoindolyl, 3H-indolyl, indolinyl,indolizinyl, indazolyl, imidazolyl, imidazol-4-yl, 2H-imidazolyl,benzimidazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,pyrimidin-2-yl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl,purinyl, pyrazolyl, pyrazol-3-yl, triazolyl, 1,2,4-triazol-1-yl,tetrazolyl, tetrazol-1-yl, thiazolyl, thiazol-4-yl, isothiazolyl,benzthiazolyl, oxazolyl, oxazol-2-yl, isoxazolyl, isoxazol-3-yl,benzoxazolyl, oxadiazolyl, 1,2,4-oxadiazol-3-yl, thiadiazolyl,pyridazin-4-yl, pyrazin-2-yl, thiophen-2-yl, furan-2-yl, pyridin-2-yl,pyridin-4-yl, pyrimidin-2-yl, and the like.

When any group is substituted with 1, 2, or 3 substituents or optionallysubstituted with 1, 2, or 3 substituents, each substituent isindependently selected from the group comprising halo, —OH, —SH, —CN,—NO₂, —NH₂, trihalomethyl, pentahaloethyl, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl,C₀-C₁₀alkyloxyC₀-C₁₀alkyl, arylC₀-C₁₀alkyloxyC₀-C₁₀alkyl,C₀-C₁₀alkylthioC₀-C₁₀alkyl, arylC₀-C₁₀alkylthioC₀-C₁₀alkyl,C₀-C₁₀alkylaminoC₀-C₁₀alkyl, arylC₀-C₁₀alkylaminoC₀-C₁₀alkyl,N-aryl-N—C₀-C₁₀alkylaminoC₀-C₁₀alkyl, C₁-C₁₀alkylcarbonylC₀-C₁₀alkyl,arylC₁-C₁₀alkylcarbonylC₀-C₁₀alkyl, C₁-C₁₀alkylcarboxyC₀-C₁₀alkyl,arylC₁-C₁₀alkylcarboxyC₀-C₁₀alkyl, C₁-C₁₀alkylcarbonylaminoC₀-C₁₀alkyl,arylC₁-C₁₀alkylcarbonylaminoC₀-C₁₀alkyl, —C₀-C₁₀alkylC(O)OR_(X), and—C₀-C₁₀alkylC(O)NR_(Y)R_(Z) wherein R_(X), R_(Y) and R_(Z) areindependently selected from hydrogen, alkyl, and aryl or R_(Y) and R_(Z)are taken together with the nitrogen to which they are attached to forma saturated cyclic or unsaturated cyclic system having 3, 4, 5, 6, 7, or8 carbon atoms with at least one substituent as defined above. A“C₀alkyl,” as in C₀-C₁₀alkyl, is a covalent bond.

The term “C₀-C₁₀alkyloxy” refers to an alkyl group having the indicatednumber of carbon atoms and attached to the molecule through an oxygenatom. In one embodiment, a C₀-C₁₀alkyloxy is a C₁-C₆alkyloxy, i.e., agroup having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples ofalkyloxy groups include methoxy, ethoxy, n-propyloxy, and isopropyloxy.Thus, the term “C₀-C₁₀alkyloxyC₀-C₁₀alkyl” refers to a C₀-C₁₀alkyloxyattached through an oxygen atom to a C₀-C₁₀alkyl which is attached tothe molecule. Likewise, the term “arylC₀-C₁₀alkyloxyC₀-C₁₀alkyl” refersto a C₀-C₁₀alkyloxy, which is substituted by aryl, attached through anoxygen atom to a C₀-C₁₀alkyl which is attached to the molecule. A“C₀alkyloxy” is —OH.

The term “C₀-C₁₀alkylthio” refers to an alkyl group having the indicatednumber of carbon atoms and attached to the molecule through a sulfuratom. In one embodiment, a C₀-C₁₀alkylthio is a C₁-C₆alkylthio, i.e., agroup having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples ofalkyloxy groups include methylthio, ethylthio, n-propylthio, andisopropylthio. Thus, the term “C₀-C₁₀alkylthioC₀-C₁₀alkyl” refers to aC₀-C₁₀alkylthio attached through a sulfur atom to a C₀-C₁₀alkyl which isattached to the molecule. Likewise, the term“arylC₀-C₁₀alkylthioC₀-C₁₀alkyl” refers to a C₀-C₁₀alkylthio, which issubstituted by aryl, attached through a sulfur atom to a C₀-C₁₀alkylwhich is attached to the molecule. A “C₀alkylthio” is —SH.

The term “C₁-C₁₀alkylcarbonyl” refers to an alkyl group having theindicated number of carbon atoms and attached to the molecule throughthe carbon atom of a carbonyl group. In one embodiment, aC₁-C₁₀alkylcarbonyl is a C₁-C₆alkylcarbonyl, i.e., a group having 1, 2,3, 4, 5, or 6 carbon atoms, including the carbonyl carbon atom. Thus,the term “C₁-C₁₀alkylcarbonylC₀-C₁₀alkyl” refers to aC₁-C₁₀alkylcarbonyl attached through the carbon atom of a carbonyl groupto a C₀-C₁₀alkyl which is attached to the molecule. Likewise, the term“arylC₁-C₁₀alkylcarbonylC₀-C₁₀alkyl” refers to a C₁-C₁₀alkylcarbonyl,which is substituted by aryl, attached through the carbon atom of acarbonyl group to a C₀-C₁₀alkyl which is attached to the molecule.

The term “C₁-C₁₀alkylcarboxy” refers to an alkyl group having theindicated number of carbon atoms, including the carboxy's carbon atom,and attached to the molecule through the carboxy group, wherein thecarboxy group has either a —C(═O)—O— or a —O—C(═O)— orientation. In oneembodiment, a C₁-C₁₀alkylcarboxy is a C₁-C₆alkylcarboxy, i.e., a grouphaving 2, 3, 4, 5, or 6 carbon atoms, including the carboxy's carbonatom. Thus, the term “C₁-C₁₀alkylcarboxyC₀-C₁₀alkyl” refers to aC₁-C₁₀alkylcarboxy attached through the carboxy group to a C₀-C₁₀alkylwhich is attached to the molecule. Likewise, the term“arylC₁-C₁₀alkylcarboxyC₀-C₁₀alkyl” refers to a C₁-C₁₀alkylcarboxy,which is substituted by aryl, attached through the carboxy group to aC₀-C₁₀alkyl which is attached to the molecule.

The term “C₀-C₁₀alkylamino” refers to an alkyl group having theindicated number of carbon atoms and attached to the molecule throughthe nitrogen atom of the amino group —N(R_(W))—, wherein R_(W) is H,C₁-C₆alkyl, or aryl. A “C₀alkylamino” is —NHR_(W). In one embodiment, aC₀-C₁₀alkylamino is a C₁-C₆alkylamino, i.e., a group having 1, 2, 3, 4,5, or 6 carbon atoms in the alkyl group and 0, 1, 2, 3, 4, 5, or 6carbon atoms in the R_(W) group. Thus, the term“C₀-C₁₀alkylaminoC₀-C₁₀alkyl” refers to a C₀-C₁₀alkylamino attachedthrough the nitrogen atom of an amino group to a C₀-C₁₀alkyl which isattached to the molecule. Likewise, the term“arylC₀-C₁₀alkylaminoC₀-C₁₀alkyl” refers to a C₀-C₁₀alkylamino, which issubstituted by aryl, attached through the nitrogen atom of an aminogroup to a C₀-C₁₀alkyl which is attached to the molecule. The term“N-aryl-N—C₀-C₁₀alkylaminoC₀-C₁₀alkyl” refers to an amine nitrogen atomsubstituted by aryl and C₀-C₁₀alkyl, that nitrogen atom being furtherattached to a C₀-C₁₀alkyl which is attached to the molecule.

The term “C₁-C₁₀alkylcarbonylamino” refers to an alkyl group having theindicated number of carbon atoms, including the carbonylamino's (i.e.,amide's) carbon atom, and attached to the molecule through the amide,group, wherein the amide group has either a —C(═O)N(R_(V))— or a—N(R_(V))C(═O)— orientation and wherein R_(V) is H or C₁-C₆alkyl. In oneembodiment, a C₁-C₁₀alkylcarbonylamino is a C₁-C₆alkylcarbonylamino,i.e., a group having 2, 3, 4, 5, or 6 carbon atoms, including theamide's carbon atom, in the alkyl group and 0, 1, 2, 3, 4, 5, or 6carbon atoms in the R_(V) group. Thus, the term“C₁-C₁₀alkylcarbonylaminoC₀-C₁₀alkyl” refers to aC₁-C₁₀alkylcarbonylamino attached through the amide group to aC₀-C₁₀alkyl which is attached to the molecule. Likewise, the term“arylC₁-C₁₀alkylcarbonylaminoC₀-C₁₀alkyl” refers to aC₁-C₁₀alkylcarbonylamino, which is substituted by aryl, attached throughthe amide group to a C₀-C₁₀alkyl which is attached to the molecule.

The term “alkylaryl” refers to an aryl group as defined above that issubstituted with 1, 2, or 3 alkyl groups as defined above; a tolyl groupis an exemplary alkylaryl. In one embodiment, an alkylaryl group is a“lower alkylaryl” group having 1, 2, or 3 alkyl groups attached to anaryl group, each alkyl group having, independently, 1, 2, 3, 4, 5, or 6carbon atoms.

The term “arylalkyl” refers to an alkyl group as defined above that issubstituted with 1, 2, or 3 aryl groups as defined above; a benzyl groupis an exemplary arylalkyl. In one embodiment, an arylalkyl group is a“lower arylalkyl” group having 1, 2, or 3 aryl groups attached to analkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

The term “heterocycloalkyl” refers to an alkyl group as defined abovethat is substituted with 1, 2, or 3 heterocyclo groups as defined above.In one embodiment, a heterocycloalkyl group is a “lowerheterocycloalkyl” group having 1, 2, or 3 heterocyclo groups attached toan alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

The term “alkylheteroaryl” refers to a heteroaryl group as defined abovethat is substituted with 1, 2, or 3 alkyl groups as defined above. Inone embodiment, a alkylheteroaryl group is a “lower alkylheteroaryl”group having 1, 2, or 3 alkyl groups attached to a heteroaryl group,each alkyl group having, independently, 1, 2, 3, 4, 5, or 6 carbonatoms.

The term “heteroarylalkyl” refers to an alkyl group as defined abovethat is substituted with 1, 2, or 3 heteroaryl groups as defined above.In one embodiment, a heteroarylalkyl group is a “lower heteroarylalkyl”group having 1, 2, or 3 heteroaryl groups attached to an alkyl grouphaving 1, 2, 3, 4, 5, or 6 carbon atoms.

The term “alkylheteroarylalkyl” refers to a heteroarylalkyl group asdefined above that is substituted with 1, 2, or 3 alkyl groups asdefined above. In one embodiment, an alkylheteroarylalkyl group is a“lower alkylheteroarylalkyl” group with each alkyl portion having,independently, 1, 2, 3, 4, 5, or 6 carbon atoms.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine, andiodine.

Should there be doubt as to the agreement of a depicted chemicalstructure and a chemical name, the depicted chemical structure governs.

The term “pharmaceutically acceptable salt” refers to those salts whichretain the biological effectiveness and properties of the “free”compounds of Formula (1). A pharmaceutically acceptable salt can beobtained from the reaction of the free base of a Compound of Formula (1)with an inorganic acid, for example, hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like, or anorganic acid, for example, sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g.,(+)-tartaric acid or (−)-tartaric acid or mixtures thereof), and thelike. Certain compounds of Formula (1) have acidic substituents and canexist as pharmaceutically acceptable salts with pharmaceuticallyacceptable bases. The present disclosure includes such salts. Examplesof such salts include metal counterion salts, such as sodium, potassium,lithium, magnesium, calcium, iron, copper, zinc, tin, silver, oraluminum salts, and organic amine salts, such as methylamine,dimethylamine, trimethylamine, diethylamine, triethylamine,n-propylamine, 2-propylamine, or dimethylisopropylamine salts, and thelike. The term “pharmaceutically acceptable salt” includes mono-saltsand compounds in which a plurality of salts is present, e.g., di-saltsand/or tri-salts. Pharmaceutically acceptable salts can be prepared bymethods known to those in the art.

Certain compounds of Formula (1) and/or their pharmaceuticallyacceptable salts can exist in more than one crystal form and the presentdisclosure encompasses each crystal form and mixtures thereof. Thesecrystal forms can be prepared by methods known to those in the art.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a Compound of Formula (1) or itspharmaceutically acceptable salt, and one or more molecules of asolvent, which is present in stoichiometric or non-stoichiometricamount. Suitable solvents include but are not limited to water, aceticacid, ethanol, methanol, isopropanol, and n-propanol. Where the solventis water, the solvate is a hydrate. Exemplary hydrates include but arenot limited to a hemihydrate, a monohydrate, a dihydrate, a trihydrate,and a tetrahydrate. In one embodiment, the solvent is pharmaceuticallyacceptable. In another embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. The present disclosure encompasses each solvateand mixtures thereof. These solvates can be prepared by methods known tothose in the art.

Certain compounds of Formula (1) may exist in different tautomeric formsor as different geometric isomers, and the present disclosure includeseach tautomer and/or geometric isomer of compounds of Formula (1) andmixtures thereof.

Certain compounds of Formula (1) may contain one or more chiral centersand exist in different optically active forms, and the presentdisclosure includes each optically active form of compounds of Formula(1) and mixtures thereof. When compounds of Formula (1) contain onechiral center, the compounds exist in two enantiomeric forms and thepresent disclosure includes both enantiomers and mixtures ofenantiomers, such as racemic mixtures. The enantiomers may be resolvedby methods known to the art, for example, by formation ofdiastereoisomeric salts which may be separated, e.g., by crystallizationor liquid chromatography. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation. When a Compound of Formula (1)contains more than one chiral center, it may exist in diastereoisomericforms. The diastereoisomeric compounds may be separated by methods knownto the art, for example, by chromatography or crystallization, and theindividual enantiomers may be separated as described above. The presentdisclosure includes each diastereoisomer of compounds of Formula (1) andmixtures thereof.

The term “isotopically enriched” refers to a Compound of Formula (1)that contains an unnatural proportion of an isotope at one or more ofthe atoms constituting the compound, and the present disclosure includeseach isotopically enriched form of compounds of Formula (1) and mixturesthereof. In certain embodiments, an isotopically enriched compoundcontains unnatural proportions of one or more isotopes, including butnot limited to hydrogen (¹H), deuterium (²H), tritium (³H), carbon-11(¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13(¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15(¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (17O), oxygen-18 (¹⁸O), fluorine-17(¹⁷F), fluorine-18 (¹⁸F), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34(³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-36(³⁶Cl), chlorine-37 (³⁷Cl), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br),iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-127 (¹²⁷I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). In another embodiment, an isotopicallyenriched compound contains unnatural proportions of one or moreisotopes, including but not limited to ¹H, ²H, ¹²C, ¹³C, ¹⁴N, ¹⁵N, ¹⁶O,¹⁷O, ¹⁸O, ¹⁷F, ³²S, ³³S, ³⁴S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, and ¹²⁷I. Inanother embodiment, an isotopically enriched compound is radioactive. Inanother embodiment, an isotopically enriched compound contains unnaturalproportions of one or more isotopes, including but not limited to ³H,¹¹C, ⁴C, ¹³N, ¹⁴O, ¹⁵O, ¹⁸F, ³⁵S, ³⁶Cl, ¹²³I, ¹²⁵I, ¹²⁹I, and ¹³¹I. Inanother embodiment, an isotopically enriched compound contains unnaturalproportions of ¹²³I, ¹²⁴I, or ¹³¹I and another isotope selected from ³H,¹¹C, ⁴C, ¹³N, ¹⁴O, ¹⁵O, ¹⁸F, ³⁵S, and ³⁶Cl. In another embodiment, anisotopically enriched compound contains an unnatural proportion of ¹²³I,¹²⁴I, and/or ¹³¹I. In another embodiment, an isotopically enrichedcompound contains an unnatural proportion of ¹²³I. In anotherembodiment, an isotopically enriched compound contains an unnaturalproportion of ¹²⁴I. In another embodiment, an isotopically enrichedcompound contains an unnatural proportion of ¹³¹I.

The term “isotopically enriched” refers to the percentage ofincorporation of a less prevalent isotope (e.g., deuterium for hydrogen)of an element at a given location in a molecule in place of a moreprevalent isotope (e.g., ¹H for hydrogen) of that element. When an atomat a particular location in a molecule is designated as a particularless prevalent isotope, it is understood that the abundance of thatisotope at that location is substantially greater than its naturalabundance.

The term “therapeutically effective amount” refers to an amount of aCompound of Formula (1) or a combination of two or more such compoundsthat inhibits, totally or partially, the progression of the treatedcondition or alleviates, at least partially, one or more symptoms of thecondition. A therapeutically effective amount can also be an amountwhich is prophylactically effective. The amount which is therapeuticallyeffective depends on the patient's gender and size, the condition to betreated, the condition's severity, and the result sought. For a givenpatient, a therapeutically effective amount can be determined by methodsknown to those in the art.

The term “patient” refers to an animal, including but not limited to amammal, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog,cat, rabbit, rat, or mouse.

The term “cancer” or “neoplastic disorder” refers to a tumor resultingfrom abnormal or uncontrolled cellular growth. Examples of cancersinclude but are not limited to breast cancers, colon cancers, colorectalcancers, prostate cancers, ovarian cancers, pancreatic cancers, lungcancers, gastric cancers, esophageal cancers, glioma cancers, andhematologic malignancies. Examples of neoplastic disorders include butare not limited to hematopoietic disorders, such as themyeloproliferative disorders, essential thrombocytosis, thrombocythemia,angiogenic myeloid metaplasia, polycythemia vera, myelofibrosis,myelofibrosis with myeloid metaplasia, chronic idiopathic myelofibrosis,the cytopenias, and pre-malignant myelodysplastic syndromes.

The term “hematologic malignancy” refers to cancer of the bone marrowand lymphatic tissue-body's blood-forming and immune system. Examples ofhematological malignancies include but are not limited tomyelodysplasia, lymphomas, leukemias, lymphomas (non-Hodgkin'slymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), andmyeloma, such as acute lymphocytic leukemia (ALL), adult T-cell ALL,acute myeloid leukemia (AML), AML with trilineage myelodysplasia, acutepromyelocytic leukemia, acute undifferentiated leukemia, anaplasticlarge-cell lymphoma, chronic lymphocytic leukemia, chronic myeloidleukemia, chronic neutrophilic leukemia, juvenile myelomonocycticleukemia, mixed lineage leukemia, myeloproliferative disorders,myelodysplastic syndromes, multiple myeloma, and prolymphocyticleukemia.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues including but not limited to acute lymphoblastic leukemia, acutemyeloid leukemia, acute myeloblastic leukemia, chronic lymphocyticleukemia, and chronic myelocytic leukemia. The leukemia can be relapsed,refractory, or resistant to conventional therapy.

The term “neurodegenerative disorder” refers to a disorder in whichprogressive loss of neurons occurs either in the peripheral nervoussystem or in the central nervous system. Examples of neurodegenerativedisorders include but are not limited to chronic neurodegenerativediseases such as diabetic peripheral neuropathy, Alzheimer's disease,Pick's disease, diffuse Lewy body disease, progressive supranuclearpalsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Dragersyndrome), motor neuron diseases including amyotrophic lateral sclerosis(“ALS”), degenerative ataxias, cortical basal degeneration,ALS-Parkinson's-Dementia complex of Guam, subacute sclerosingpanencephalitis, Huntington's disease, Parkinson's disease, multiplesclerosis, synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 andolivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy(Kennedy's disease), primary lateral sclerosis, familial spasticparaplegia, Wernicke-Korsakoffs related dementia (alcohol induceddementia), Werdnig-Hoffmann disease, Kugelberg-Welander disease,Tay-Sach's disease, Sandhoff disease, familial spastic disease,Wohifart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, and prion diseases (includingCreutzfeldt-Jakob, Gerstmann-Straussler-Schcinkcr disease, Kuru andfatal familial insomnia). Other conditions also included within themethods of the present disclosure include age-related dementia and otherdementias, and conditions with memory loss including vascular dementia,diffuse white matter disease (Binswanger's disease), dementia ofendocrine or metabolic origin, dementia of head trauma and diffuse braindamage, dementia pugilistica, and frontal lobe dementia. Also otherneurodegenerative disorders resulting from cerebral ischemia orinfarction including embolic occlusion and thrombotic occlusion as wellas intracranial hemorrhage of any type (including but not limited toepidural, subdural, subarachnoid, and intracerebral), and intracranialand intravertebral lesions (including but not limited to contusion,penetration, shear, compression, and laceration). Thus, the term“neurodegenerative disorder” also encompasses acute neurodegenerativedisorders such as those involving stroke, traumatic brain injury,schizophrenia, peripheral nerve damage, hypoglycemia, spinal cordinjury, epilepsy, anoxia, and hypoxia.

In certain embodiments, the neurodegenerative disorder is selected fromAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,age-related memory loss, senility, and age-related dementia. In anotherembodiment, the neurodegenerative disorder is Alzheimer's disease, alsocharacterized as an amyloidosis. Thus, other embodiments of thedisclosure relate to the treatment or prevention of other amyloidosisdisorders which share features, including, but not limited to,hereditary cerebral angiopathy, normeuropathic hereditary amyloid,Down's syndrome, macroglobulinemia, secondary familial Mediterraneanfever, Muckle-Wells syndrome, multiple myeloma, pancreatic- andcardiac-related amyloidosis, chronic hemodialysis arthropathy, Finnishamyloidosis, and Iowa amyloidosis.

The term “pharmaceutically acceptable carrier” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or an organof a patient without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable carriers areknown in the art; see, e.g., Pharmaceutical Preformulation andFormulation (Gibson, ed., 2^(nd) Ed., CRC Press, Boca Raton, Fla.,2009); Handbook of Pharmaceutical Additives (Ash and Ash, eds., 3^(rd)Ed., Gower Publishing Co., Aldershot, U K, 2007); Remington'sPharmaceutical Sciences (Gennaro, ed., 19^(th) Ed., Mack Publishing,Easton, Pa., 1995); and Handbook of Pharmaceutical Excipients (Amer.Pharmaceutical Ass'n, Washington, D C, 1986).

In another embodiment, a pharmaceutical composition is formed from aCompound of Formula (1) and a pharmaceutically acceptable carrier by amethod known in the art. Thus, another embodiment relates to apharmaceutical composition comprising a Compound of Formula (1) and apharmaceutically acceptable carrier. Such a composition is useful fortreating or preventing cancer or a neurodegenerative disorder, e.g., ina patient in need thereof.

Another embodiment relates to a method for treating or preventing canceror a neurodegenerative disorder, comprising administering to a patientin need thereof a therapeutically effective amount of a Compound ofFormula (1). Another embodiment relates to a method for treating orpreventing cancer or a neurodegenerative disorder, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprising a Compound of Formula(1). Another embodiment relates to a method for treating cancer or aneurodegenerative disorder, comprising administering to a patient inneed thereof a therapeutically effective amount of a Compound of Formula(1). Another embodiment relates to a method for treating cancer or aneurodegenerative disorder, comprising administering to a patient inneed thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a Compound of Formula (1). Another embodimentrelates to a method for preventing cancer or a neurodegenerativedisorder, comprising administering to a patient in need thereof atherapeutically effective amount of a Compound of Formula (1). Anotherembodiment relates to a method for preventing cancer or aneurodegenerative disorder, comprising administering to a patient inneed thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a Compound of Formula (1). Another embodimentrelates to the use of a Compound of Formula (1) in the manufacture of amedicament useful for treating cancer or a neurodegenerative disorder orfor preventing cancer or a neurodegenerative disorder.

Another embodiment relates to a method for the inhibition of Hsp90,comprising contacting Hsp90 with an Hsp90 function inhibiting amount ofa Compound of Formula (1). An exemplary determination of an Hsp90function inhibiting amount is provided in the example below entitled“Hsp90 Binding Assay.” In one embodiment, the IC₅₀ determined by the“Hsp90 Binding Assay” provided herein is less than 10 μM. In anotherembodiment, the IC₅₀, determined by the “Hsp90 Binding Assay” providedherein is less than 1 μM. In another embodiment, the IC₅₀ determined bythe “Hsp90 Binding Assay” provided herein is ≤0.1 μM. Another embodimentrelates to the use of a Compound of Formula (1) in formulating apharmaceutical composition for the inhibition of Hsp90.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention as described and claimed herein. Variations of the invention,including the substitution of all equivalents now known or laterdeveloped, that would be within the purview of those in the art, andchanges in formulation or changes in experimental design, are to beconsidered to fall within the scope of the invention incorporatedherein.

4 EXAMPLES

Certain examples below relate to the synthesis of illustrative compoundsof the disclosure.

N-(benzo[d][1,3]dioxol-5-yl)acetamide (B)

To a solution of 3,4-(methylenedioxy)aniline (5.0 g, 36.5 mmol) in AcOH(75 mL) was added acetic anhydride (30 mL). The reaction mixture wasstirred at a temperature of about 25° C. for about 16 hours, then pouredinto a saturated NaHCO₃ solution and filtered. The filtrate wasextracted with ethyl acetate to provide B in quantitative yield whichwas used without further purification.

¹H NMR (500 MHz, DMSO-d₆, δ): 9.82 (s, 1H), 7.29 (d, J=1.4 Hz, 1H), 6.93(dd, J=8.3, 1.4 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 5.97 (s, 2H), 1.99 (s,3H).

MS (ESI): m/z=180.1 [M+H]⁺.

N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (C)

A 1.0 M solution of iodine monochloride in methylene chloride (46.5 mL)was added dropwise to a solution of B (6.4 g, 35.8 mmol) in methylenechloride (42 mL) and acetic acid (7 mL). The reaction mixture wasstirred for about 16 hours then washed with saturated sodium thiosulfateand brine. The methylene chloride solution was dried over MgSO₄,filtered and concentrated under reduced pressure to provide a residuewhich was purified by chromatography (CH₂Cl₂:EtOAc, 20:1) to provide C(6.0 g, 55% yield).

¹H NMR (500 MHz, DMSO-d₆ δ): 9.33 (s, 1H), 7.37 (s, 1H), 6.96 (s, 1H),6.07 (s, 2H), 2.01 (s, 3H).

MS (ESI): m/z=328.0 [M+Na]⁺.

6-Iodobenzo[d][1,3]dioxol-5-amine (D)

A solution of C (3.2 g, 10.5 mmol) and NaOH (21 g, 525 mmol) in ethanol(420 mL) and water (96 mL) was refluxed for 4 h. The reaction mixturewas cooled and concentrated under reduced pressure to provide a residuethat was partitioned between methylene chloride and water. The organiclayer was washed with water, dried over MgSO₄, filtered and concentratedunder reduced pressure to provide a residue which was purified bychromatography (hexane:CH₂Cl₂, 7:3) to provide D (2.1 g, 76% yield).

¹H NMR (500 MHz, CDCl₃, δ): 7.05 (s, 1H), 6.38 (s, 1H), 5.87 (s, 2H),3.85 (br s, 2H).

MS (ESI): m/z=264.0 [M+H]⁺.

6-Iodo-N,N-dimethylbenzo[d][1,3]dioxol-5-amine (E)

To a mixture of D (200 mg, 0.7604 mmol), paraformaldehyde (228 mg, 7.604mmol), and molecular sieves (2 g) in methylene chloride (4 ml) and AcOH(0.435 mL, 7.604 mmol) was added NaBH₃CN. The mixture was heated to 50°C. for 2 h. To the reaction mixture was added water and the organiclayer was separated and the aqueous layer was further extracted withmethylene chloride a few times. The organic layers were combined andwashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to provide E (181 mg, 82% yield) which was used withoutfurther purification.

¹H NMR (500 MHz, CDCl₃, δ): 7.25 (s, 1H), 6.74 (s, 1H), 5.95 (s, 2H),2.65 (s, 6H).

MS (ESI): m/z=292.1 [M+H]⁺.

8-(6-(Dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (F)

A mixture of 8-mercaptoadenine (160 mg, 0.978 mmol), neocuproine hydrate(40.7 mg, 0.196 mmol), CuI (36.4 mg, 0.196 mmol), sodium tert-butoxide(0.184 mg, 1.91 mmol), E (370 mg, 1.27 mmol) and DMF (4 mL) were heatedat 115° C. for 32 h. The solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7N), 10:1)to provide F (123 mg, 39% yield).

¹H NMR (500 MHz, CDCl₃/MeOH-d₄, δ): 8.15 (s, 1H), 6.86 (s, 1H), 6.81 (a,1H), 5.97 (s, 2H), 2.72 (s, 6H).

MS (ESI): m/z=331.3 [M+H]⁺.

9-(2-Bromoethyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine(G)

F (29 mg, 0.0878 mmol), Cs₂CO₃ (42.9 mg, 0.1317 mmol), 1,2-dibromoethane(82.5 mg, 37.8 μL, 0.439 mmol) in DMF (0.6 mL) was stirred for 1.5 h ata temperature of about 25° C. Then additional Cs₂CO₃ (14 mg, 0.043 mmol)was added and the mixture stirred for an additional 20 min. The mixturewas dried under reduced pressure and the residue purified by preparatoryTLC (CH₂Cl₂:MeOH:AcOH, 15:1:0.5) to provide G (24 mg, 63% yield).

¹H NMR (500 MHz, CDCl₃/MeOH-d₄, δ): 8.24 (s, 1H), 6.81 (s, 1H), 6.68 (s,1H), 5.96 (s, 2H), 4.62 (t, J=6.9 Hz, 2H), 3.68 (t, J=6.9 Hz, 2H), 2.70(s, 6H).

MS (ESI): m/z=437.2/439.1 [M+H]⁺.

8-(6-(Dimethylamino)benzo[d][1.3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine(DZ4-132)

G (24 mg, 0.0549 mmol) and neopentylamine (239 mg, 2.7 mmol) in DMF(0.50 mL) was stirred at a temperature of about 25° C. for about 16hours. Solvent was removed under reduced pressure and the resultingresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7N), 20:1) toprovide 20.6 mg (85% yield) of DZ4-132.

¹H NMR (500 MHz, CDCl₃/MeOH-d₄, δ): 8.16 (s, 1H), 6.73 (a, 1H), 6.55 (s,1H), 5.88 (s, 2H), 4.27 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.61(s, 6H), 2.28 (s, 2H), 0.79 (s, 9H).

¹³C NMR (125 MHz, CDCl₃/MeOH-d₄, δ): 154.8, 152.9, 151.8, 149.4, 149.2,148.7, 145.2, 120.0, 118.7, 111.6, 102.9, 102.3, 62.4, 50.1, 45.7, 44.1,31.9, 28.1.

MS (ESI): m/z=444.3 [M+H]⁺.

9-(3-Bromopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine(H)

F (60 mg, 0.1818 mmol), Cs₂CO₃ (88.8 mg, 0.2727 mmol),1,3-dibromopropane (184 mg, 93 μL, 0.909 mmol) in DMF (2 mL) was stirredfor 40 min. at a temperature of about 25° C. The mixture was dried underreduced pressure and the residue purified by preparatory TLC(CH₂Cl₂:MeOH:AcOH, 15:1:0.5) to provide H (60 mg, 73% yield).

¹H NMR (500 MHz, CDCl₃, δ): 8.26 (s, 1H), 6.84 (br s, 2H), 6.77 (s, 1H),6.50 (s, 1H), 5.92 (s, 2H), 4.35 (t, J=7.0 Hz, 2H), 3.37 (t, J 6.6 Hz,2H), 2.68 (s, 6H), 2.34 (m, 2H).

MS (ESI): m/z=451.1/453.1 [M+H]⁺.

8-(6-(Dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamine)propyl)-9H-purin-6-amine(DZ4-134)

H (30 mg, 0.0665 mmol) and isopropylamine (196 mg, 283 μL, 3.3 mmol) inDMF (1 mL) was stirred at a temperature of about 25° C. for about 16hours. Solvent was removed under reduced pressure and the resultingresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7N), 20:1) toprovide 21.8 mg (78% yield) of DZ4-134.

¹H NMR (500 MHz, CDCl₃, δ): 8.24 (s, 1H), 6.69 (s, 1H), 6.39 (s, 1H),5.98 (br s, 2H), 5.83 (s, 2H), 4.23 (t, J=6.9 Hz, 2H), 2.68 (septet,J=6.3 Hz, 1H), 2.61 (s, 6H), 2.48 (t, J=6.8 Hz, 2H), 1.95 (m, 2H), 0.99(d, J=6.3 Hz, 6H).

¹³C NMR (125 MHz, CDCl₃, δ): 155.3, 153.6, 152.3, 148.7, 147.7, 147.0,145.4, 121.1, 120.8, 109.7, 103.1, 102.3, 49.6, 45.9, 44.2, 42.1, 30.5,23.1.

MS (ESI): m/z=430.2 [M+H]⁺.

9-(3-(tert-Butylamino)propyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine(DZ4-135)

H (30 mg, 0.0665 mmol) and tert-butylamine (243 mg, 350 μL, 3.3 mmol) inDMF (1 mL) was stirred at a temperature of about 25° C. for about 16hours. Solvent was removed under reduced pressure and the resultingresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7N), 20:1) toprovide 18.5 mg (63% yield) of DZ4-135.

¹H NMR (500 MHz, CDCl₃, δ): 8.25 (s, 1H), 6.69 (s, 1H), 6.40 (s, 1H),5.88 (br s, 2H), 5.83 (s, 2H), 4.23 (t, J=7.0 Hz, 2H), 2.62 (s, 6H),2.43 (t, J=6.8 Hz, 2H), 1.91 (m, 2H), 0.98 (s, 9H).

MS (ESI): m/z=444.2 [M+H].

Hsp90 Binding Assay:

For the binding studies, fluorescence polarization (FP) assays wereperformed similarly as was previously reported [Du et al. (2007)“High-throughput screening fluorescence polarization assay fortumor-specific Hsp90” J. Biomol. Screen 12:915-924]. Briefly, FPmeasurements were performed on an Analyst GT instrument (MolecularDevices, Sunnyvale, Calif.). Measurements were taken in black 96-wellmicrotiter plates (Corning #3650) where both the excitation and theemission occurred from the top of the well. A stock of 10 μM cy3B-GM wasprepared in DMSO and diluted with HFB buffer (20 mM Hepes (K), pH 7.3,50 mM KCl, 2 mM DTT, 5 mM MgCl₂, 20 mM Na₂MoO₄, and 0.01% NP40 with 0.1mg/mL BGG). The test compounds were dissolved in DMSO and added atseveral concentrations to the HFB assay buffer containing both 6 nMcy3B-GM and transgenic mouse brain lysate (6 μg JNPL3 lysate) or humancancer cell lysate (3 μg SKBr3 lysate) in a final volume of 100 μL.Drugs were added to triplicate wells. Free cy3B-GM (6 nM cy3B-GM), boundcy3B-GM (6 nM cy3B-GM+lysate, as indicated above) and buffer onlycontaining wells (background) were included as controls in each plate.Plates were incubated on a shaker at 4° C., and polarization valuesmeasured at 24 h. Percentage inhibition was calculated as follows: (%Control)=100−((mP_(c)−mP_(f))/(mP_(b)−mP_(f)))×100, where mP_(c) is therecorded mP from compound wells, mP_(f) is the average recorded mP fromcy3B-GM-only wells, and mP_(b) is the average recorded mP from wellscontaining both cy3B-GM and lysate, and plotted against values ofcompetitor concentrations. The inhibitor concentration at which 50% ofbound cy3B-GM was displaced was obtained by fitting the data using anonlinear regression analysis as implemented in Prism 4.0 (GraphPadSoftware).

In these assays, the following simplified Hsp90 binding grading wasused: I≥10 μM; 10 μM>II>1 μM; 1 μM>III>0.1 μM; IV≤0.1 μM for C₅₀. Asshown, each of the compounds tested showed an IC₅₀ of less than or equalto 0.1 μM which is a high level of activity.

Table 1 shows results of testing for Compounds DZ4-132, DZ4-134, andDZ4-135, and a comparison compound (PU—H71) of the formula

In interpreting these test results, it will be appreciated that bindingto Hsp90 for activity in the treatment of cancer or neurodegenerativedisorders is desirable. In contrast, it is generally undesirable to havebinding to hERG since binding to hERG can result in undesirable cardiacside effects. Therefore, having a low value for binding to Hsp90 and ahigh value for binding to hERG is desirable, bearing in mind that theunits for the two measurement are different.

TABLE 1 Compound SKBr3 Binding Affinity (nM) hERG binding (uM) DZ4-13210.0 5.5 DZ4-134 55.3 11.0 DZ4-135 45.4 14.0 PU-H71 20 1

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those in the art and are intended to fallwithin the scope of the appended claims. A number of references havebeen cited, the entire disclosures of which are incorporated herein byreference for all purposes.

What is claimed:
 1. A method for treating cancer or a neurodegenerative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein: (a) each of Z₁, Z₂ and Z₃ is independently CH or N; (b) Y is S; (c) Xa and Xb are O; (d) Xc is —CH₂—; (e) X₂ is —NR₁R₂, wherein R₁ and R₂ are each independently H, C₁₋₆ alkyl, C₂-C₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl; (f) X₄ is hydrogen or halogen; (g) R is —R₁₀—NH—R₁₁ wherein R₁₀ is ethylene or propylene, and (i) R₁₁ is isopropyl or t-butyl, or (ii) R₁₁ is a branched alkyl, Z₁, Z₂ and Z₃ are each N, and R₁ and R₂ are each independently alkyl which has 1, 3, 4, 5, or 6 carbon atoms, C₂-C₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, wherein the neurodegenerative disorder is selected from the group consisting of spinal and bulbar muscular atrophy (Kennedy's disease), Alzheimer's Disease (AD), dementia of head trauma and diffuse brain damage, dementia pugilistica, traumatic brain injury, frontal lobe dementia, Parkinson's disease, and Huntington disease, and wherein the cancer is selected from the group consisting of hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, and ovarian cancer.
 2. The method of claim 1, wherein X₂ is dimethylamine.
 3. The method of claim 1, wherein R₁₁ is neopentyl.
 4. The method of claim 1, wherein R₁₁ is isopropyl.
 5. The method of claim 1, wherein R₁₁ is t-butyl.
 6. The method of claim 1, wherein Z₁, Z₂ and Z₃ are each N.
 7. The method of claim 1, wherein Z₁, Z₂ and Z₃ are each N, X₂ is dimethylamine, Y is S, R₁₀ is ethylene, R₁₁ is neopentyl, and X₄ is H.
 8. The method of claim 1, wherein Z₁, Z₂ and Z₃ are each N, X₂ is dimethylamine, Y is S, R₁₀ is propylene, R₁₁ is isopropyl, and X₄ is H.
 9. The method of claim 1, wherein Z₁, Z₂ and Z₃ are each N, X₂ is dimethylamine, Y is S, R₁₀ is propylene, R₁₁ is t-butyl, and X₄ is H.
 10. The method of claim 1, wherein the method is for treating a neurodegenerative disorder.
 11. The method of claim 1, wherein the method is for treating cancer.
 12. The method of claim 7, wherein the method is for treating a neurodegenerative disorder.
 13. The method of claim 7, wherein the method is for treating cancer.
 14. The method of claim 8, wherein the method is for treating a neurodegenerative disorder.
 15. The method of claim 8, wherein the method is for treating cancer.
 16. The method of claim 9, wherein the method is for treating a neurodegenerative disorder.
 17. The method of claim 9, wherein the method is for treating cancer.
 18. The method of claim 1, wherein the neurodegenerative disorder is dementia of head trauma and diffuse brain damage, dementia pugilistica, and/or traumatic brain injury.
 19. The method of claim 1, wherein the hematopoietic disorders are selected from myeloproliferative disorders, myelofibrosis, polycythemia vera, and essential thrombocytosis.
 20. The method of claim 10, wherein the neurodegenerative disorder is Alzheimer's Disease (AD). 